Programmatic Themes

Theme 1: Precision Oncology

Drs. Eric Small (PI), CharlesRyan, DavideRuggero, and RobertBlelloch work on the West Coast Prostate Cancer Dream Team (WCDT) supported by Stand Up 2 Cancer (SU2C), The Prostate Cancer Foundation, and the American Association of Cancer Research. UCSF serves as the coordinating center for this multicenter grant, with the goal of identifying adaptive pathways associated with resistance in castration-resistant prostate cancer, and in particular with the identification of biological pathways associated with resistance to abiraterone acetate, enzalutamide, and other potent AR-targeting agents. In total, the program has collected over 160 metastatic tumor samples, with cancer isolated by laser capture microdissection, and subsequently sequenced. Pathways for targeting are identified by (1) prior work undertaken by WCDT investigators, (2) in vitro study of new potential target pathways, (3) in silico analysis of existing prostate cancer data sets by the knowledge exchange working group, or (4) through novel findings from the pathway analysis of WCDT biopsies.

Drs.Ryan, Small, and Lawrence Fong have overseen the development and conduct of approximately 15 clinical trials in advanced prostate cancer. Trials with the following overarching themes have been developed: PI3 kinase signaling; novel vaccine development; and studies in abiraterone resistance, chemotherapy, and augmentation of the efficacy of abiraterone-based treatment (Aggarwal et al., Clin Genitourin Cancer, 2014; Kim et al., Clin Cancer Res, 2014; Ryan et al., Lancet Oncol, 2015). Investigator-initiated trials have been opened to test ARN509, a direct AR-antagonist, as monotherapy for primary hormonal therapy, and testing the impact of increasing abiraterone dose when patients with mCRPC progress on standard dose. Clinical trials in patients with abiraterone-refractory prostate cancer have been undertaken: one randomizes patients to either Enzalutamide or Cabozantanib, and one evaluates the single agent efficacy of Selinexor, an inhibitor of the XPO-1 nuclear export complex. Both trials integrate the analysis of pre-treatment tissue obtained through the WCDT. Dr. Ryan has received funding to undertake a program entitled Network Enriched Crossover Trials (NEXT) that will integrate the efforts of a number of junior faculty and their investigational approaches with the tissue collection platforms afforded through the SU2C efforts.

Dr. John Witte has evaluated the potentially pleiotropic effect of the high penetrance prostate cancer HOXB13 G84E mutation among 83,285 non-Hispanic White participants from the Kaiser Permanente Research Program on Genes, Environment, and Health. This study found that the age-specific risk of prostate cancer among G84E mutation carriers was higher than among non-carriers, and this difference increased with age. The G84E mutation was also associated with an increase in risk for the fourteen other most common cancers considered collectively and more so in cases diagnosed with multiple cancer types, both those including and not including prostate cancer, strongly suggesting pleiotropic effects (Hoffmann et al., PLoS Genet, 2015).

Drs. Carroll (PI), June Chan and Matthew Cooperberg (co-PIs), Witte, Jeff Belkora, and colleagues continue to work on their Transformative Impact Award from the DOD to improve prognostication at the time of biopsy among men with low-risk prostate cancer. The goal is to build and evaluate a novel integrated risk prediction tool and decision aid, and to enhance informed decision-making regarding active surveillance for low-risk prostate cancer. The study will include discovery and validation cohorts, and a community-based randomized clinical trial to evaluate the effect of the risk model and decision aid on treatment choices, as well as patient-reported decision quality/decisional regret, anxiety, and uncertainty.

Drs. John Kurhanewicz, Daniel Vigneron, Carroll, Small, and Max Meng completed a first-in-man study of hyperpolarized 13C pyruvate, testing the safety and image quality in localized prostate cancer patients. A phase II trial will be launched in the first quarter of 2015, with the goal of describing the clinical utility of this imaging biomarker.

Dr. Blelloch and his lab are focused on the role of microRNAs on prostate cancer progression in vivo (funded by a DOD grant). Dr. Blelloch has found that miRNAs are not necessary for early establishment of prostate tumors but are essential for progression to carcinoma. At the cellular level, miRNAs play a role in enabling basal cell expansion by inhibiting senescence. Drs. Blelloch and Carroll have developed serum microRNAs as biomarkers in low-risk prostate cancer patients (NCI R21 grant). They have identified a microRNA signature that could predict adverse pathology in patients that were identified as low risk based on other pre-surgical criteria. Identification of adverse pathology increases prognosis to intermediate risk, separating them from true low-risk patients (Wang et al., PLoS One, 2014).

Theme 3: Biology and Therapeutic Targets

Dr.Fong continues to assess the impact of cancer immunotherapy on antigen-specific responses in both animal models and in patients. His laboratory has examined the mechanism by which sipuleucel-T may improve survival in prostate cancer patients (Fong et al., J Natl Cancer Inst, 2014). Drs. Fong, Small, and Ryan have completed a trial in which patients with localized prostate cancer receive neo-adjuvant sipuleucel-T and demonstrated that this treatment lead to a >3-fold increase in CD4 T cells in the prostates of treated patients. Moreover, these immune cells were primary localized at the tumor rim. These results demonstrate for the first time that sipuleucel-T treatment can modulate an immune response within the tumor microenvironment.

Dr. Seo continues to work with Drs. Bin Liu and Marc Shuman in developing novel antibody-based drugs and imaging probes for prostate cancer. In the past year, they have been focused on preparing the data for human translation of therapeutic antibody drug conjugates, and investigating pharmacokinetics of different antibodies using radiolabeling techniques and positron emission tomography (PET) imaging. Dr. Liu is developing novel antibody-based drugs and imaging probes for prostate cancer. In the past year, their progress has been focused on developing a therapeutic antibody drug conjugates.

Dr. Davide Ruggero and his lab continue to focus on the PI3K-AKT-mTOR signaling pathway and Myc. His lab has shown that 4EBP1, the central inhibitor of cap-dependent translation, is a critical regulator of both prostate cancer initiation and maintenance downstream of mTOR signaling in vivo. In addition, elevated 4EBP1 levels have been shown to underlie resistance of tumor cells to PI3K-AKT-mTOR pathway inhibitors, and that dampening total 4EBP1 expression levels is sufficient to reverse resistance. Together, these findings reveal an unexpected molecular program controlling cell type-specific 4EBP1 transcription coupled to regulation of global protein synthesis rates that renders each epithelial cell type of the prostate uniquely sensitive or resistant to inhibitors of the PI3K-AKT-mTOR signaling pathway.